1051 - M480, an Oral Fxr Agonist, is Superior to Cyclosporine a and Equally Efficacious as Anti-Il-12/23 in the Adoptive Transfer Model of IBD Colitis

Introduction: Sacral nerve stimulation (SNS) was reported to improve TNBS-induced colitis in rats.However, the routes of action need to be investigated.Our aim of this study was to investigate if SNS anti-inflammatory effect is mediated by the local sacral splanchnic nerves efferent-colon and/or the spinal cord-brain stem-vagal efferent-colon pathway.Methods: SNS electrodes were implanted unilaterally at S3 sacral nerve of rats to investigate the routes of action of SNS.The sacral and vagal nerves were cut in distinct locations at the same time of electrode implantation.Rats were subjected to 1-Bilateral truncal vagotomy 2-Proximal-Sacrotomy (proximal to the implanted electrodes), 3-Mid-Sacrotomy (middle to the implanted electrodes), 4-Distal-Sacrotomy (distal to the implanted electrodes) and 5-Splenic neurectomy.Rats were administrated with TNBS intra-rectally.Five days after TNBS-induced colitis, rats were divided into different groups and subjected to different treatment for 10 days as follows: Sham-SNS (control group with no stimulation), SNS, Vagotomy, Vagotomy+SNS, Distal-Sacrotomy, Distal-Sacrotomy+SNS, Mid-Sacrotomy, Mid-Sacrotomy+SNS, Proximal-Sacrotomy, Proximal-Sacrotomy+SNS, Splenic-Neurectomy, Splenic-Neurectomy+SNS and another control group with rectal injection of saline and without any treatment.SNS was performed 1 hours daily.The autonomic function was assessed by spectral analysis of heart rate variability (HRV) derived from the electrocardiogram.Results: 1) SNS and Distal-Sacrotomy+SNS, Splenic Neurectomy+SNS but not Vagotomy+SNS significantly decreased the DAI and MPO activity compared with sham-SNS.However, the anti-inflammatory effects of SNS group were more potent than Distal-Sacrotomy+SNS and Splenic Neurectomy+SNS.2) Spectral analysis of HRV showed a decrease in vagal activity (HF) following TNBS treatment; however, SNS was able to normalize the vagal activity in both Distal-Sacrotomy+SNS and Splenic-Neurectomy+SNS groups.3) SNS significantly increase Acetyl choline in colon tissues in both Distal-Sacrotomy+SNS, and Splenic-Neurectomy+SNS but not the Vagotomy and Vagotomy+SNS groups.4) SNS elevated anti-inflammatory cytokines (IL-2, IL-10) and decreased pro-inflammatory cytokines (IL-17A, TNF a) in SNS and Distal-Sacrotomy+SNS groups in comparison with Sham-SNS.5) SNS effectively increased the number of c-fos positive cells in NTS area in SNS group than sham-SNS.This demonstrated that the spinal cord-brain stem-vagal efferent-colon pathway is actively involved in antiinflammatory pathway.Conclusion: SNS exerts an anti-inflammatory effect on TNBSinduced colitis by enhancing vagal activity mediated via the spinal cord-brain stem-vagal efferent-colon pathway.